US3812153A - Process for producing monoalkanoyl-fluoresceins - Google Patents
Process for producing monoalkanoyl-fluoresceins Download PDFInfo
- Publication number
- US3812153A US3812153A US00312386A US31238672A US3812153A US 3812153 A US3812153 A US 3812153A US 00312386 A US00312386 A US 00312386A US 31238672 A US31238672 A US 31238672A US 3812153 A US3812153 A US 3812153A
- Authority
- US
- United States
- Prior art keywords
- reaction
- benzene
- solvent
- product
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/44—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving esterase
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B11/00—Diaryl- or thriarylmethane dyes
- C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
- C09B11/06—Hydroxy derivatives of triarylmethanes in which at least one OH group is bound to an aryl nucleus and their ethers or esters
- C09B11/08—Phthaleins; Phenolphthaleins; Fluorescein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N31/00—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods
- G01N31/22—Investigating or analysing non-biological materials by the use of the chemical methods specified in the subgroup; Apparatus specially adapted for such methods using chemical indicators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2334/00—O-linked chromogens for determinations of hydrolase enzymes, e.g. glycosidases, phosphatases, esterases
- C12Q2334/40—Triphenylmethane dye chromogens, e.g. fluorescein derivatives
Definitions
- This invention relates to a process for the preparation of higher monoalkanoylfiuoresceins represented by the formula 0 o oC@:j 0 h cannons from the aromatic solvent with a selective non-solvent for the product.
- halide can be any of the halides, i.e., iodide, chloride, fluoride or bromide, however, because of its ready availability, the chloride is the preferred starting material. Thus, in its most preferred embodiment, decanoyl chloride is the starting material.
- the reaction should be carried out under essentially anhydrous conditions in order to avoid the side reactions resulting from the presence of moisture. If non-anhydrous conditions are used, the yields are adversely affected.
- the reaction should also be carried out in an inert atmosphere in order to avoid the formation of co-products and minimize side reactions.
- Suitable inert atmospheres are argon and nitrogen, with nitrogen preferred.
- the solvent in which the reaction is carried out should be an aprotic organic solvent which is easily removed under vacuum, catalyzes the reaction of fluorescein with acid halides and dissolves the product.
- Dimethylformamide (DMF) has been found to be most suitable, however, dimethylsulfoxide (DMSO) or hexamethyl phosphoric triamide (HMPT) can also be used.
- the amount of solvent used in the reaction is important since the yields of the monoalkanoylfluorescein are affected. It has been found that on a volume basis from 8 to 30 volumes of solvent per volume of fluorescein are suitable for use in this process, with from 10 to 15 volumes preferred. 10 volumes is most preferred when DMF is the solvent and monodecanoylfluorescein is the product.
- the temperature at which the process is operable is in the range of from about 15 C. to about 30 C. with room temperature, e.g., about 20 C. to 25 C. preferred. Higher temperatures result in undesirable side reactions with production of increasing amounts of the dialkanoylfluorescein.
- the selective aromatic solvent must be a non-solvent for filuorescein and a solvent for the monoalkanoylfluoresceins.
- Typical of such solvents are benzene and toluene. Preferred for use in this invenare difficult to make in sufiicient purity and high enough yields to make them available in commercial quantities at a reasonable cost.
- the alkanoyl halide which is used as the source of the alkanoyl moiety in the process is a higher alkanoyl halide containing from 10 to 18 carbon atoms.
- Preferred for use in this invention is decanoyl halide since the resulting tion is benzene.
- the adsorbing filtering medium must be such that the products are adsorbed thereon and the impurities remain in the filtrate which is discarded.
- Typical of such adsorbing filtering media are alumina and silica gel.
- Silica gel is one volume of diethyl ether.
- Preferable is a volume ratio of 4 parts aromatic solvent to one of diethyl ether.
- the preferred aromatic solvents are benzene or toluene.
- non-solvent for the product must be added.
- the most suitable nonsolvent is hexane.
- the dissolved product Prior to filtration through the adsorbing filter medium, the dissolved product is treated wtih a basic material to neutralize any unreacted acid present.
- a suitable neutralizing agent is sodium bicarbonate, however, other alkali metal bicarbonates can also be used.
- the reaction is run for a time sufficient to complete the reaction. Generally it is run overnight, however, somewhat shorter or longer times are suitable. Generally, the reaction is run from two to twelve hours.
- Example 1 25.0 g. (0.075 mole) of fluorescein and 490 ml. of dimethylformamide were added to a 1 l. 3-neck flask equipped with stirrer, Herschberg dropping funnel and a nitrogen atmosphere. A mixture of 13.6 g. of decanoylchloride (0.071 mole) in 50 ml. of dimethylformamide was added, while stirring at room temperature, to the flask through the dropping funnel, over a period of hours, gradually effecting complete solution. The dimethylformamide was then removed at reduced pressure (0.5 mm.), 400 ml. of benzene was added, the resulting mixture stirred 20 min., filtered and washed with two 40 ml. portions of benzene.
- the resulting presscake contained fiuorescein.
- the combined benzene filtrates were washed with two 80 ml. portions of 0.1 N sodium bicarbonate solution and 60 ml. of water, dried over sodium sulfate, then calcium sulfate and filtered through a pad of 120 g. of silica gel contained in a 600 ml. sintered glass funnel.
- the silica gel was washed with four 100 ml. portions of benzene-ether 4:1 v./v., each wash-filtrate being kept separate.
- Example 2 25.0 g. (0.075 mole) of fluorescein and 250 ml. of dimethylformamide were added to a 1 l. 3-neck flask equipped with stirrer, Herschberg dropping funnel and a nitrogen atmosphere. A mixture of 13.6 g. of decanoylchloride (0.071 mole) in 40 ml. of dimethylformamide was added, while stirring at room temperature, to the flask through the dropping funnel, over a period of 10 hours, gradually effecting complete solution. The dimethylformamide was then removed at reduced pressure (0.5 mm.), 400 ml. of benzene was added, the resulting mixture stirred 20 min., filtered and washed with two 40 ml. portions of benzene.
- decanoylchloride 0.071 mole
- the resulting presscake contained fiuorescein.
- the combined benzene filtrates were washed with two 80 ml. portions of 0.1 N sodium bicarbonate solution and 60 ml. of water, dried over sodium sulfate, then calcium sulfate and filtered through a pad of 120 g. of silica gel contained in a 600 ml. sintered glass funnel.
- the silica gel was washed with five 100 ml. portions of benzene-ether 4:1 v./v. Concentration of the combined filtrates yielded 31.3 gms. of crude product.
- the benzeneether residues were combined and crystallized by solution in ml. of boiling benzene followed (after removal from heat) by addition of 340 ml.
- a method for preparing compounds represented by the formula 0 0 o l I o wmncni C 0 OH wherein n is a whole number from 8 to 16 inclusive, comprising reacting a higher alkanoyl halide containing from 10 to 18 carbon atoms with fluorescein at a temperature of from about 15 C. to about 30 C.
- reaction takes place in an aprotic organic solvent selected from dimethylformamide, dimethylsulfoxide or hexamethyl phosphoric triamide in which the reactants are slowly brought into contact, the resulting reaction mixture after completion of the reaction is neutralized with a basic material, and the product is isolated by filtering on an adsorbing filter medium selected from alumina and silica gel then eluted with an aromatic solvent-ether mixture containing from 2 to 15 volumes of aromatic solvent and one volume of ether and finally crystallized therefrom with hexane.
- an aprotic organic solvent selected from dimethylformamide, dimethylsulfoxide or hexamethyl phosphoric triamide in which the reactants are slowly brought into contact
- the resulting reaction mixture after completion of the reaction is neutralized with a basic material
- the product is isolated by filtering on an adsorbing filter medium selected from alumina and silica gel then eluted with an aromatic solvent-ether mixture containing from 2 to 15 volumes of aromatic solvent and one volume of ether and
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US00312386A US3812153A (en) | 1972-12-05 | 1972-12-05 | Process for producing monoalkanoyl-fluoresceins |
IT31090/73A IT1001670B (it) | 1972-12-05 | 1973-11-08 | Procedimento per la preparazione di mono alcanoil fluoresceine |
DE2359099A DE2359099A1 (de) | 1972-12-05 | 1973-11-27 | Verfahren zur herstellung von monoalkanoylfluoresceine |
NL7316275A NL7316275A (xx) | 1972-12-05 | 1973-11-28 | |
FR7342986A FR2208895B1 (xx) | 1972-12-05 | 1973-12-03 | |
JP48134455A JPS4987735A (xx) | 1972-12-05 | 1973-12-03 | |
BE138464A BE808167A (fr) | 1972-12-05 | 1973-12-04 | Procede pour la preparation de mondalcanoyl-fluoresceines |
AT1014473A AT332872B (de) | 1972-12-05 | 1973-12-04 | Verfahren zur herstellung von monoalkanoylfluoresceine |
GB5612573A GB1431470A (en) | 1972-12-05 | 1973-12-04 | Process for the manufacutre of monoalkanoylfluoresceins |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US00312386A US3812153A (en) | 1972-12-05 | 1972-12-05 | Process for producing monoalkanoyl-fluoresceins |
Publications (1)
Publication Number | Publication Date |
---|---|
US3812153A true US3812153A (en) | 1974-05-21 |
Family
ID=23211205
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US00312386A Expired - Lifetime US3812153A (en) | 1972-12-05 | 1972-12-05 | Process for producing monoalkanoyl-fluoresceins |
Country Status (9)
Country | Link |
---|---|
US (1) | US3812153A (xx) |
JP (1) | JPS4987735A (xx) |
AT (1) | AT332872B (xx) |
BE (1) | BE808167A (xx) |
DE (1) | DE2359099A1 (xx) |
FR (1) | FR2208895B1 (xx) |
GB (1) | GB1431470A (xx) |
IT (1) | IT1001670B (xx) |
NL (1) | NL7316275A (xx) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4304720A (en) * | 1980-04-30 | 1981-12-08 | Merck & Co., Inc. | Fluorescein esters and ethers and the preparation thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2040033A1 (de) * | 1970-08-12 | 1972-02-17 | Boehringer Mannheim Gmbh | Fluorescein-monocarbonsaeureester und Verfahren zur Herstellung derselben |
-
1972
- 1972-12-05 US US00312386A patent/US3812153A/en not_active Expired - Lifetime
-
1973
- 1973-11-08 IT IT31090/73A patent/IT1001670B/it active
- 1973-11-27 DE DE2359099A patent/DE2359099A1/de active Pending
- 1973-11-28 NL NL7316275A patent/NL7316275A/xx unknown
- 1973-12-03 FR FR7342986A patent/FR2208895B1/fr not_active Expired
- 1973-12-03 JP JP48134455A patent/JPS4987735A/ja active Pending
- 1973-12-04 GB GB5612573A patent/GB1431470A/en not_active Expired
- 1973-12-04 AT AT1014473A patent/AT332872B/de not_active IP Right Cessation
- 1973-12-04 BE BE138464A patent/BE808167A/xx unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4304720A (en) * | 1980-04-30 | 1981-12-08 | Merck & Co., Inc. | Fluorescein esters and ethers and the preparation thereof |
Also Published As
Publication number | Publication date |
---|---|
GB1431470A (en) | 1976-04-07 |
AT332872B (de) | 1976-10-25 |
FR2208895B1 (xx) | 1978-09-22 |
FR2208895A1 (xx) | 1974-06-28 |
DE2359099A1 (de) | 1974-06-12 |
IT1001670B (it) | 1976-04-30 |
BE808167A (fr) | 1974-06-04 |
JPS4987735A (xx) | 1974-08-22 |
ATA1014473A (de) | 1976-02-15 |
NL7316275A (xx) | 1974-06-07 |
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